1. Field of the Invention
The present invention involves pyrazolidinyl compounds and methods and pharmaceutical compositions that comprise such compounds. Compounds of the invention can be effective to modulate the function of the ubitquitylation system, regulate p53 and Mdm2 stability and activity as well as to act as therapeutic agents in a variety of indications, particularly to treat cancer as well to treat viral infections, particularly to treat retroviral-infected mammalian cells.
2. Background
The development of cancer can depend on the accumulation of specific genetic alterations that allow aberrant cell proliferation, including growth of tumor cells. Protection from such aberrant growth is provided by several mechanisms that work by inducing apoptotic cell death in cells undergoing oncogenic changes. Therefore, for a tumor cell to survive, it must acquire genetic alterations that perturb the link between abnormal growth and cell death. The p53 tumor suppressor protein can induce apoptotic cell death and plays a pivotal role in tumor suppression. Wild type p53 functions as a transcriptional regulator to coordinately control multiple pathways in cell cycling, apoptosis, and angiogenesis.
Loss of the ability to induce p53 or other loss of p53 activity can lead to uncontrolled cell proliferation of the affected cells and tumor growth. In approximately 50% of human cancers, a wild type p53 gene is nevertheless retained. In such cancers, the defect that frequently occurs is a failure to stabilize and activate p53 to thereby prevent tumor development.
The Mdm2 protein plays an important role in targeting the degradation of p53 in normal cells to allow normal growth and development. In particular, inhibition of Mdm2 is required to allow activation of a p53 response. In tumors with wild type p53, defects can occur that lead to increased Mdm2 activity, whereby p53 function cannot be induced.
Ubiquitin-mediated proteolysis is an important pathway of non-lysosomal protein degradation that controls the timed destruction of a number of cellular regulatory proteins including p53. See Pagano, 1997 FASEB J. 11:1067. Ubiquitin is an evolutionary highly conserved 76-amino acid polypeptide which is abundantly present in eukaryotic cells. The ubiquitin pathway leads to the covalent attachment of poly-ubiquitin chains to target substrates which are then degraded by a multi-catalytic proteasome complex.
A number of the steps of regulating protein ubiquitination are known. In particular, initially the ubiquitin activating enzyme (E1) forms a high energy thioester linkage with ubiquitin. Ubiquitin is then transferred to a reactive cysteine residue of one of many ubiquitin conjugating enzymes known as Ubc or ubiquitin E2 enzymes. The final transfer of ubiquitin to a target protein involves one of many ubiquitin protein ligases (E3s). Mdm2 is such a ubiquitin ligase that mediates the transfer of ubiquitin to p53. See also WO05047476.
The human immunodeficiency virus (HIV) including HIV type 1 (HIV-1, also referred to as HTLV-III LAV or HTLV-III/LAV) and, to a lesser extent, human immunodeficiency virus type 2 (HIV-2) is the etiological agent of the acquired immune deficiency syndrome (AIDS) and related disorders. Barre-Sinoussi, et al., Science, 220:868-871 (1983).
Efforts to identify certain agents that can inhibit retroviral replication by modulating ubiquitination of a host cell protein has been reported. U.S. Patent Publication 2005/0112562.
It thus would be desirable to have new compounds that have use in treatment of undesired cell proliferation, including in treatment against cancer cells, as well as for treatment against viral infections, particularly to treat retroviral-infected mammalian cells. It would be especially desirable to have new compounds that could modulate or stabilize p53 activity by inhibiting Mdm2-mediated ubiquitination.